Puzzle of "French Paradox" Natural Product Solved

September 21, 2004

La Jolla, CA – Researchers at the Salk Institute have successfully bioengineered resveratrol synthase from chalcone synthase, a biosynthetic protein enzyme found in all higher plants. Their findings appear in the September issue of Chemistry & Biology.

Using the tools of structural biology, Michael B. Austin, a graduate student at the Salk Institute and the University of California, San Diego, solved the three dimensional structure of resveratrol synthase and compared its shape to its relative, chalcone synthase. Austin, part of a research team led by Professor Joseph P. Noel of the Salk Institute, has now uncovered the crucial differences between these related plant enzymes.

Besides illuminating molecular mechanisms of plant evolution, this study also has agricultural and nutraceutical significance. Noel and colleagues used their new knowledge to convert a chalcone synthase from alfalfa into an efficient resveratrol-producing factory, merely by changing a few amino acids (the building blocks of proteins). This biotechnological advance permits the engineering of natural resveratrol production into crop plants, via a small modification of that plant's own chalcone synthase gene, as occurs naturally in grapes, blueberries and a few other plants.

Resveratrol, a beneficial component of red wine, is thought to partly contribute to the improved cardiovascular effects associated with the moderate consumption of red wine (the "French Paradox"). Laboratory studies with resveratrol have demonstrated an impressive list of health benefits, including roles as anti-oxidants, cancer preventative agents, blood thinners, and blood pressure lowering compounds. Recently, resveratrol was shown to significantly increase life span in both fruit flies and yeast, suggesting an additional role in human diets as a promising anti-aging natural chemical.

"We want to continue to explore taking what occurs naturally in plants and work toward producing this rare molecule in other crop plants," said Noel. "Ultimately, our research could lead to producing resveratrol in a wide array of fruits and vegetables."

The impressive health benefits of resveratrol consumption are a lucky accident, however, as grapes actually produce resveratrol in order to defend against fungal invasion. Salk researchers have now deciphered the three-dimensional structure of the rare plant enzyme that creates this remarkable but rare molecule, and in the process they resolved a long-standing scientific puzzle: the crucial differences between chalcone synthases and their resveratrol-producing relatives, the much rarer stilbene synthases.

Scientists realized decades ago that chalcones and stilbenes, two important classes of plant natural products with very different properties, were produced by different but closely related proteins. All higher plants possess chalcone synthase, as chalcone-derived natural chemicals fulfill a number of important biological functions in plants including roles in plant fertility, disease resistance and flower color. Conversely, production of resveratrol and other rare anti-fungal stilbenes occurs in just a few plant species, including grapevines, peanuts, blueberries and some pine trees.

The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.